BACKGROUND: The mammalian Major Histocompatibility Complex (MHC) is a genetic region containing highly polymorphic genes with immunological functions. MHC class I and class II genes encode antigen-presenting molecules expressed on the cell surface. The MHC class II sub-region contains genes expressed in antigen presenting cells. The antigen binding site is encoded by the second exon of genes encoding antigen presenting molecules. The exon 2 sequences of these MHC genes have evolved under the selective pressure of pathogens. Interspecific differences can be observed in the class II sub-region. The family Equidae includes a variety of domesticated, and free-ranging species inhabiting a range of habitats exposed to different pathogens and represents a model for studying this important part of the immunogenome. While equine MHC class II DRA and DQA loci have received attention, the genetic diversity and effects of selection on DRB and DQB loci have been largely overlooked. This study aimed to provide the first in-depth analysis of the MHC class II DRB and DQB loci in the Equidae family. RESULTS: Three DRB and two DQB genes were identified in the genomes of all equids. The genes DRB2, DRB3 and DQB3 showed high sequence conservation, while polymorphisms were more frequent at DRB1 and DQB1 across all species analyzed. DQB2 was not found in the genome of the Asiatic asses Equus hemionus kulan and E. h. onager. The bioinformatic analysis of non-zero-coverage-bases of DRB and DQB genes in 14 equine individual genomes revealed differences among individual genes. Evidence for recombination was found for DRB1, DRB2, DQB1 and DQB2 genes. Trans-species allele sharing was identified in all genes except DRB1. Site-specific selection analysis predicted genes evolving under positive selection both at DRB and DQB loci. No selected amino acid sites were identified in DQB3. CONCLUSIONS: The organization of the MHC class II sub-region of equids is similar across all species of the family. Genomic sequences, along with phylogenetic trees suggesting effects of selection as well as trans-species polymorphism support the contention that pathogen-driven positive selection has shaped the MHC class II DRB/DQB sub-regions in the Equidae.

Ceitec MU Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Ceitec VFU RG Animal Immunogenomics Brno Czech Republic

Ceitec VRI RG Animal Cytogenomics Brno Czech Republic

Centre for GeoGenetics Natural History Museum of Denmark Øster Voldgade 5 7 1350K Copenhagen Denmark

Department of Animal Genetics Veterinary and Pharmaceutical University Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Department of Genetics and Reproductive Biotechnologies Veterinary Research Institute Brno Czech Republic

Laboratoire d'Anthropobiologie Moléculaire et d'Imagerie de Synthèse CNRS UMR 5288 Université de Toulouse Université Paul Sabatier 31000 Toulouse France

National Centre for Biomolecular research Faculty of Science Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Zoo Prague U Trojského zámku 120 3 171 00 Praha 7 Czech Republic

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$a Klumplerova, Marie $u Department of Animal Genetics, Veterinary and Pharmaceutical University, Brno, Czech Republic $u Ceitec VFU, RG Animal Immunogenomics, Brno, Czech Republic

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$a Genetic diversity, evolution and selection in the major histocompatibility complex DRB and DQB loci in the family Equidae / $c M. Klumplerova, P. Splichalova, J. Oppelt, J. Futas, A. Kohutova, P. Musilova, S. Kubickova, R. Vodicka, L. Orlando, P. Horin

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$a BACKGROUND: The mammalian Major Histocompatibility Complex (MHC) is a genetic region containing highly polymorphic genes with immunological functions. MHC class I and class II genes encode antigen-presenting molecules expressed on the cell surface. The MHC class II sub-region contains genes expressed in antigen presenting cells. The antigen binding site is encoded by the second exon of genes encoding antigen presenting molecules. The exon 2 sequences of these MHC genes have evolved under the selective pressure of pathogens. Interspecific differences can be observed in the class II sub-region. The family Equidae includes a variety of domesticated, and free-ranging species inhabiting a range of habitats exposed to different pathogens and represents a model for studying this important part of the immunogenome. While equine MHC class II DRA and DQA loci have received attention, the genetic diversity and effects of selection on DRB and DQB loci have been largely overlooked. This study aimed to provide the first in-depth analysis of the MHC class II DRB and DQB loci in the Equidae family. RESULTS: Three DRB and two DQB genes were identified in the genomes of all equids. The genes DRB2, DRB3 and DQB3 showed high sequence conservation, while polymorphisms were more frequent at DRB1 and DQB1 across all species analyzed. DQB2 was not found in the genome of the Asiatic asses Equus hemionus kulan and E. h. onager. The bioinformatic analysis of non-zero-coverage-bases of DRB and DQB genes in 14 equine individual genomes revealed differences among individual genes. Evidence for recombination was found for DRB1, DRB2, DQB1 and DQB2 genes. Trans-species allele sharing was identified in all genes except DRB1. Site-specific selection analysis predicted genes evolving under positive selection both at DRB and DQB loci. No selected amino acid sites were identified in DQB3. CONCLUSIONS: The organization of the MHC class II sub-region of equids is similar across all species of the family. Genomic sequences, along with phylogenetic trees suggesting effects of selection as well as trans-species polymorphism support the contention that pathogen-driven positive selection has shaped the MHC class II DRB/DQB sub-regions in the Equidae.

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$a Splichalova, Petra $u Department of Animal Genetics, Veterinary and Pharmaceutical University, Brno, Czech Republic $u Ceitec VFU, RG Animal Immunogenomics, Brno, Czech Republic

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$a Oppelt, Jan $u Ceitec VFU, RG Animal Immunogenomics, Brno, Czech Republic $u Ceitec MU, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic $u National Centre for Biomolecular research, Faculty of Science, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic

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$a Futas, Jan $u Department of Animal Genetics, Veterinary and Pharmaceutical University, Brno, Czech Republic $u Ceitec VFU, RG Animal Immunogenomics, Brno, Czech Republic

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$a Kohutova, Aneta $u Department of Animal Genetics, Veterinary and Pharmaceutical University, Brno, Czech Republic $u Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic

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$a Musilova, Petra $u Department of Genetics and Reproductive Biotechnologies, Veterinary Research Institute, Brno, Czech Republic $u Ceitec VRI, RG Animal Cytogenomics, Brno, Czech Republic

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$a Kubickova, Svatava $u Department of Genetics and Reproductive Biotechnologies, Veterinary Research Institute, Brno, Czech Republic $u Ceitec VRI, RG Animal Cytogenomics, Brno, Czech Republic

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$a Vodicka, Roman $u Zoo Prague, U Trojského zámku 120/3, 171 00, Praha 7, Czech Republic

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$a Orlando, Ludovic $u Laboratoire d'Anthropobiologie Moléculaire et d'Imagerie de Synthèse, CNRS UMR 5288, Université de Toulouse, Université Paul Sabatier, 31000, Toulouse, France $u Centre for GeoGenetics, Natural History Museum of Denmark, Øster Voldgade 5-7, 1350K, Copenhagen, Denmark

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$a Horin, Petr $u Department of Animal Genetics, Veterinary and Pharmaceutical University, Brno, Czech Republic. horin@dior.ics.muni.cz $u Ceitec VFU, RG Animal Immunogenomics, Brno, Czech Republic. horin@dior.ics.muni.cz

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